The treatment of acute and chronic pain is extremely important in medicine. There is currently a worldwide demand for additional highly effective pain treatment. The urgent need for action for patient-oriented and purposeful treatment of acute and chronic pain, this being taken to mean the successful and satisfactory treatment of pain for the patient, is documented in the large number of scientific papers which have recently appeared in the field of applied analgesics and fundamental research work on nociception.
Opioids have been used for many years as analgesics for the treatment of pain, however they give rise to a series of side effects, for example addiction and dependency, respiratory depression, gastrointestinal inhibition, nausea, vomiting, urinary retention and obstipation.
Millions of people suffer from pain. The pain may be minor, such as headaches, acute lower back pain, and acute muscle pain, or severe, such as chronic pain. Chronic pain may be associated with cancer treatment, HIV, diabetes, or other conditions. Chronic pain can be difficult to treat, with many chronic pain sufferers noting that their pain is not well controlled with current pain medications or that their medications have significant associated adverse effects (for example, nausea and vomiting, dependence, tolerance, etc.). Chronic pain is pain that extends beyond the expected period of healing. Acute pain generally is of limited duration and subsides quickly again after removal of the stimulus triggering it.
One problem in combating chronic and acute pain are the side-effects, in particular respiratory depression, of μ-opioids, such as morphine or fentanyl, which are highly effective against chronic and acute pain. Unfortunately, it is often not possible to effectively treat pain without opioids. Therefore, because of the fear of respiratory depression and further side-effects typical of μ-opioids in many cases this results in opioids being used to an inadequate extent in severe pain, for example in cancer patients (Davis et al., Respiratory Care Journal 1999, 44 (1)).
In an attempt to address the problem of chronic pain management, intrathecal and epidural infusion pumps and catheters have been developed. These modalities are aimed at intermittent, continuous, or near continuous delivery of a variety of liquid analgesic agents which include opioids, local anesthetics and drugs with other mechanisms. Many infusion pumps are totally implantable, which helps to reduce the risk of infection when compared to the long-term use of external systems. The infusion pump may also be programmable to allow patients or their clinicians to adjust dosing amounts or daily delivery schedule, helping to meet a patient's changing needs.
Epidural or intrathecal delivery of opioids has the advantage that it is likely to decrease the incidence of opioid side effects that are mediated through peripheral or supraspinal mechanisms (e.g. obstipation, GI dysfunction, components of nausea and vomiting, potentially components of urinary retention etc.). Despite this intent no opioid, to date, has been restricted to the central nervous system thereby eliminating the possibility that peripherally mediated opioid side effects might occur.
During childbirth, many women receive combinations of local anesthetic and opioids to prevent the pain associated with childbirth via epidural catheter. The process of inserting the epidural catheter can on occasion inadvertently cannulate an epidural blood vessel which can lead to an unintentional systemic administration of the intended epidural solution.
The use of opioids in young infants requires special consideration and expertise. Newborn infants, especially premature babies or those who have neurologic abnormalities or pulmonary disease, are susceptible to apnea and respiratory depression when systemic opioids are used (Purcell-Jones et al., The use of opioids in neonates. A retrospective study of 933 cases. Anaesthesia 1987; 42(12):1316-20). The infant's metabolism is altered so that the elimination half-life is longer and the blood-brain barrier is more permeable (Collins et al., Fentanyl pharmacokinetics and hemodynamic effects in preterm infants during ligation of patent ductus arteriosus. Anesth Analg. 1985; 64(11):1078-80; Lynn et al., Morphine pharmacokinetics in early infancy. Anesthesiology 1987; 66(2):136-9). Both factors result in young infants having higher in-brain concentrations of opioids for a given dose than do mature infants or adults. Inadvertent maternal systemic exposure to opioids during the delivery process can lead to respiratory depression and the need for resuscitation of the newborn infant.
There is thus an urgent need for new medicaments for the treatment of pain, that limit the side effects associated with opioids and offer the potential of greater safety where newborn infants are involved.